Pharmaceutical composition for treating mental fatigue containing arginine-potassium phospho citro glutamate and method of using the same

ABSTRACT

THIS INVENTION RELATES TO ARGININE-POTASSIUM PHOSPHOCITRO GLUTAMATE AND ITS PREPARATION. AS WELL AS PHARMACEUTICAL COMPOSITION CONTAINING THE SAME AND THE ISE OF THE LATTER IN THE TREATMENT OF PHYSICAL AND PHYSIC ASTHENIA.

United Sta s Pa h a 3,809,759 u PHARMACEUTICAL COMPOSITION 1 FOR TREAT- .ING MENTAL FATIGUE CONTAINING ARGI- NINE-POTASSIUM PHOSPHO CITRO GLUTA- MATE AND METHOD OF USING THE SAME 1 Dominique Bocher, 11 Rue du Moulin Vert, Paris 14c, 'France, and Robert Faure,'49 Ter, Rue de la Baste,

Vaux le Penil, France No Drawing. Filed Nov. 19, 1970, Ser. No. 91,195 Claims priority, applicagtitarizl srance, Nov. 21, 1969,.

Int. Cl. A61k 27/00 US. Cl. 424-317 11 Claims ABSTRACT OF THE DISCLOSURE Patented May 7., 1974 Theprocess of this invention makes it possible to obtain arginine-potassium phospho citro glutamatein the crude state, witha very highyield.

Qualitative identification of the arginine-potassium phospho citro glutamate was performed in the following manner:-

t (1) 1 Reaction with nitro molyhdic acid indicated the presence ofthePO, T anion in solution. Actually, an absorption band is noted in the infrared at 1050 cm.-

;(2) Reaction withDeniges' reagent and potassium permanganate gave a white precipitate which shows the presence of citric acid.

This invention relates to arginine-potassium phospho Y citro glutamate and its preparation, as well as a pharmaceutical composition containing the same andthe use of the latter in the treatment of physical and psychic asthenia.

This invention relates to, by way of novel compound, arginine-potassium phospho citro glutamate and a method for preparing the same and its use in the treatment of physical and psychic asthenia. f

This compound has the empirical formula and can be represented by the following developed formula:

C. In aqueous solution, it is in the form of a clear I solution with a pH of 5.8. The novel compound is insoluble in ethyl alcohol, but is watersoluble at a rate of 59.2% by weight. 1

The present invention is also directed to a process for preparing arginine-potassium phospho citro ,glut amate which comprises reacting in a first stage phosphoric acid and glutamic acid diluted in water with the base, L-arginine, to produce arginine phospho glutamate.

Sepanately, potassium monobasic citrate solution is prepared by reacting citric acid with potash. 1

v (3) Action of hot ninhydrin on the novel compound of this invention gives. an intense blue shade, which establishes the presence of arginine and! glutamic acid.

(4) The mauve coloring of flame test shows the presence of potassium.

Thearginine-potassium phospho citro glutamate of this invention presents to ultraviolet, in 1% solution, a maximum absorption at 224 mg, the light intensity transmitted being 1.4%.

, Quantitative identification of the arginine-potassium phospho citro glutamate was performed .by the following determinations:

(1) Determination of arginine was performed by colorimetry in the presence of oxine and hypobromite in an alkaline medium. The coloring was stabilized by urea which destroys the excess hypobromite. This determination gives a percentage of arginine corresponding to theory, namely, 59.40%.

(2) Determination of glutamic acid was performed by transformation into the corresponding hydroxanic acid by sodium nitrite and hydrolasamine, followed by colorimetric determination in the presence of ferric chloride. This determinationgives a percentage of glutamic acid corresponding to theory, namely, 12.55%.

2(3) Determination of phosphorus was performed by phosphomolybdic acid reaction and acidimetric titration by soda after dissolving in hydrochloric acid. This determination yields a percentage of phosphorus corresponding to theory, namely, 8.34%.

In the second stage, the potassium monobasic citrate solution is then poured slowly, withvigorous stirring, into the arginine phospho glutamatesolution, thetempera'tu're ofwhich has been brought to between about .60-65 C Stirring is continued for twenty minutes at this temperature and'the reaction mixture is then permitted to stand for an hour while the temperature thereof returns to ambient temperature.

The cooled solution is then filtered, and the filtrate is concentrated, thereby crystallizing the arginine-potassium (4)"Determination of citric acid was performed by transformation into betacetoglutaric acid and gravimetry. This determination gives a percentage of citric acid corresponding to theory, namely, 16.39%.

1 (5) Determination of potassium was performed by flame photometry. This determination gave a percentage of potassium corresponding to theory, namely, 3.32%.

Over-all determination of the nitrogen content was performed bythe Codex method (N being collected in the form of NH then titrated by sulfuric acid). This determ'ination'yields a total percentage of nitrogen corresponding to theory, namely, 20.31%.

The following exemplifies a method of preparing arginine-potassium phospho citro glutamate according to the present invention.

PROCESS OF PREPARING ARGININE-POTAS; SIUM PHOSPHO CITRO GLUTAMATE To obtain-50 kg., or 43 moles of arginine-potassium phospho citro glutamate, an arginine phospho glutamate solution is prepared in a first stage by mixing together 29.928 kg. of pure L-arginine, 6.321 kg. of pure glutamic acid, 4.950 kg. of phosphoric acid and liters of purified water.

To this resulting solution of arginine phospho glutamate thereis added in a second stage with vigorous stirring and at a temperature between about 60 and 65 C., a solu-- tion of potassiumcitrate which is prepared by dissolving 9.036 kg. of monohydrated citric acid and 2.832 kg. of 85 potash, in pellet form, in 18 liters of purified water. After the potassium citrate has been added, stirring is continued for twenty'minutes while 'rnairltaining the temperature at about 60 65' C. Then stirring is 'discon- Thereafter, the solution is filtered and the filtrate'is concentrated, thereby crystallizing 1 the arginine-potassium phospho citro glutamate.

The arginine-potassium phospho citro glutamatecan advantageously be recrystallized in water and when obtained as described above it is present'in the form of a white microcrystalline powder having. a melting pointof 162-163 C. v

By determination according to the Karl Fischer method it presents a moisture rate of The present invention also has for its'object a pharmaceutical composition containing the arginine-potassium phospho citro. glutamate of this invention in 'a'suitable pharmaceutical 'excipient. I

Heretofore', it has been known that certain arginine salts have been proposed for therapeutic use. For example, arginine phosphate andarginine citrate have been employed in therapeutic compositions.

As has been clearly indicated above, the arginine-potassium phospho citro glutamate according to the present invention is not a simple association of' the principal agents already known, but as the'potential balance of its formula proves, a new molecule having its own physical and chemical properties, and quite exact therapeutic indications.

The arginine-potassium phospho citro glutamate according to the invention is recommended more particularly for its refreshing and energy action, both in human and animal therapeutics.

Pharmacological studies made on rats and guinea pigs have made it possible to show the properties of argininepotassium phospho citro glutamate. These properties are- .(3) By its dynamogenic properties, it increases the resistance of the organism to fatigue, aggressions and infections; I n

(4) By its pshyco-detoxicating properties, it improves. the memory and intellectual output without causing psychic excitation; l

(5) By its psycho-energetic properties, it makes possible a psychic improvement and promotes sleep, vphysical and intellectual effort, by its action on cerebral. metabolism; and

i. H r 'J- P sium phospho citro glutamate. When in solid form, such as in'the'form'of granules, pills, tablets,boluses-or'cap sules, such ingestible solid compositions generally contain, per unit, between 50 mg. and l g. of active compound. Representative excipients, which make it possible to achieve soIidingestibIe compositions containing the active compound, are those conventionally used for similar types of composition. Examples of such excipients are described, for instance, in U.S. Pat. 2,888,380.

v The present invention also has for its object a process of treating physical and psychic asthenia which comprises administering orally a pharmaceutical composition-com taining arginine-potassium phospho citro glutamate in an i ingestibleor pharmaceutical excipient.

The period of treatment isgenerally between ten and forty-five days, with daily-doses of theorder of 0.5 to 5 g';, taking account of the non-toxicity of said argininepotassium phospho citro-glutamate. Adult doses are generally between 2'and'fl5 g. while childrensdoses are normally between 0.05 g. and 2 g.

The activity of the arginine-potassium phospho citro glutamate has been further demonstrated by considerable clinical testing on humans. This clinical study hasmade it possible to demonstrate the therapeutic action of argin- 4 inc-potassium phospho citro glutamate in the case of physical and;-psychic asthenia, convalescence, slowness in school and mental fatigue.

The following pharmaceutical compositions are given to illustrate the present invention:

EXAMPLE 1 A syrup is made for children by preparing the following mixture:

' F. ture:

(6) It further makes possible a rapid neutrali z'ationiof nitrogen metabolic wastes, reducing ammoniemia and facilitating hepatic synthesis of urea.

In the toxicological study conducted on' rat's, guinea pigs and rabbits (acute, subacute and-chronic toxicity) phospho citro glutamate, the remainder being essentially 5w liquid carrier such as an aqueous solution" having a fragrant or pleasing aroma. The aqueous solution-generally contains about 5-40 weight percent of the arginine-potas- Ampoules having a volume of 10 cc. are prepared for adults by making the following mixtures;

Arginine-potassium phospho citro glutamate g 2 Sucrose g 3 Honey scent g 1.l0 Caramel' scent L .l .g 0.30 Distilled water ml 10 l EXAMPLE 3 Tablets are prepared by making the following mix- Arginine-potassium phospho citro glutamate 0.500 Lactose sufficientfor 0.660

v EXAMPLE 4 Tablets are prepared by making the following mixture:

Arginine-potassium phospho citro glutamate 0.500 Honey scent 0.025 Caramel scent -L--- 0.075 Crystallized white sugar 2.200 Tragacanth mucilage "0.200

What is claimed is: I I

II' A pharmaceutical composition for treating mental fatigue comp'rising a pharmaceutical excipient and arginine-potassium phospho citro glutamatepresent in an amount" effective toLtreat-sa'id mental fatigue, said amount ranging between about "0.05 to percent by weight of said composition.

2. The composition of claim 1 in liquid form.

3. The composition of claim 2 containing between 5 and 40 weight percent arginine-potassium citro glutamate.

4. The composition of claim 1 in solid form.

5. The composition of claim 4 containing said arginineabout 0.5-5 g. per day of arginine-potassium phospho citro glutamate in an ingestible pharmaceutical excipient.

11. The process of claim 10 wherein said argininepotassium phospho citro glutamate is administered for a potassium phospho citro glutamate in amounts ranging 5 Period ranging between 10 and 45 daysbetween 5 and 1,000 mg. per unit.

6. The composition of claim 4 in the form of granules. 7. The composition of claim 4 in the form of pills. 8. The composition of claim 4 in the form of tablets.

9. The composition of claim 4 in the form of capsules. 1O

10. A process for treating mental fatigue comprising orally administering to a human in an amount effective to treat said mental fatigue, said amount ranging from References Cited UNITED STATES PATENTS 2,888,380 5/1959 Brown et a1. 424-37 VINCENT D. TURNER, Primary Examiner US. Cl. X.R. 260-534 E 

